Effects of orotic acid-induced non-alcoholic fatty liver on the pharmacokinetics of metoprolol and its metabolites in rats

Purpose: Preliminary study results have shown that rats with non-alcoholic fatty liver disease (NAFLD) induced by 1% orotic acid-containing diet have decreased hepatic CYP2D activity. This study aims to evaluate the possible pharmacokinetic changes in NAFLD as a result of reduced metabolic activity of CYP2D. Methods: The pharmacokinetics of metoprolol and its metabolites, O-desmethyl metoprolol (DMM) and α-hydroxy metoprolol (HM), was investigated in NAFLD and control rats following intravenous (1 mg/kg) and oral (2 mg/kg) administration of metoprolol. The hepatic CYP2D expression was also investigated. Results: NAFLD rats had lower CYP2D expression (by 36.6%) and slower intrinsic clearance (CL_int) of metoprolol and formation of HM (by 40.1% and 37.2%, respectively). There were no significant changes in the pharmacokinetics of metoprolol and its metabolites following intravenous administration. In contrast, oral administration of metoprolol resulted in significantly increased total area under plasma concentration-time curve (AUC) of metoprolol (by 127%) and decreased metabolite formation ratios (AUC_DMM/AUC_Metoprolol [by 42.8%], AUC_HM/AUC_Metoprolol [by 35.0%]) in NAFLD rats. Moreover, these changes were well correlated with severity of steatosis as quantified by hepatic triglyceride contents. Conclusions: NALFD can lead to a reduction in the hepatic CL_int of a drug if it is a substrate of the CYP2D subfamily. The decreased clearance may result in elevated drug concentrations and increased exposure.